WHO Grade IV Glioma: Glioblastoma multiforme (GBM) is the most common and deadly form of primary brain cancer in adults. The current standard treatment of GBM consists of surgery followed by combined chemo- and radiation therapy (RT); despite this aggressive approach, the median survival time remains just over one year. The primary goal of this research proposal is to therefore develop a novel RadioTheranostic approach to treat GBM that employs for the first time Gold- and SuperParamagnetic Iron Oxide (SPIO)-nanoparticle loaded polymeric Micelles (GSMs) and utilizes Radiation and a Glioma-restricted IL13Ra2-targeting ligand to selectively deliver radiation-enhancing and MR-imagable nanoparticles. With well aligned radiotherapeutic and diagnostic (RadioTheranostic) properties, GSMs will be customized, characterized and modeled for intracranial tumor treatment and imaging. The analyses will include the effects of precisely delivered RT in augmenting spatially targeted GSM accumulation within brain tumors. Leveraging our combined expertise in radiobiology, neuro-oncology, orthotopic and transgenic glioma models, molecular imaging, nanotechnology and bioengineering we will test the central hypothesis that administration of novel GSM formulations will significantly improve the targeting and efficacy of RT for GBM with little to no added toxicity and fulfill the following specific aims Aim 1. Synthesize and characterize GSMs with complementary therapeutic and diagnostic capabilities. Aim 2. Determine the optimal timing between RT and GSM administration for maximal selective GSM accumulation within intracranial tumors, MR imaging, and RT dose enhancement. Aim 3. Characterize IL13Ra2-targeted GSMs for imaging and treatment of Glioblastoma. We have marshaled a versatile team with the requisite experience and expertise to successfully test our hypothesis and address our specific aims. These studies together should together help facilitate a breakthrough advance in the treatment of GBM, while helping to fulfill the RadioTheranostic potential of GSMs for this highly intractable and deadly brain tumor.